Inward rectifier potassium (Kir) channels are essential for salivary gland function, blood feeding, and vector competence in mosquitoes

Controlling mosquito-borne diseases is becoming more complicated as resistance to conventional insecticides is spreading among mosquito populations. Thus, there is a need to increase the “tool box” for arbovirus control by supplementing existing control programs with novel strategies that focus on interrupting the viral disease cycle in the vector. Despite the importance of salivary proteins for mosquito blood feeding, seminal studies suggested saliva is not a prerequisite for blood feeding that curbed efforts away from testing relevance of salivary gland specific ion channels as targets for mosquito antifeedants. Our data challenge this long-standing paradigm by providing evidence that saliva secretion is indeed required for blood feeding as manual transection of the salivary duct eliminated the ability to blood feed on artificial hosts. Next, we aimed to identify a therapeutic target that would eliminate the burden of mosquito feeding through inhibition of salivary gland function. Pharmacological modulation of inward rectifier potassium (Kir) channels reduced the secretory activity of mosquito salivary glands with two Kir channel modulators eliminating saliva secretion of individual mosquitoes. Importantly, the reduced secretory activity of the salivary gland led to inhibition of blood meal acquisition, altered feeding behavior, and nearly eliminated horizontal transmission and acquisition of Dengue virus. These data provide a new paradigm for mechanisms driving mosquito blood feeding and begin to validate salivary gland Kir channels as novel antifeedant targets for mosquitoes that could guide the development of novel therapeutics to interrupt the arbovirus life cycle.